A randomised controlled trial comparing FMT (Fecal Microbiota Transplantation) after budesonide or placebo in patients with active ulcerative colitis

Despite an increasing number of active drugs against Inflammatory Bowel Disease (IBD) (ulcerative colitis and Crohn's disease), treatment results are disappointing far a subset of patients. In general, patients with ulcerative colitis are treated with with mesalazine (with or without prednisolone as induction). If mesalazine alone appears insufficient, a thiopurine (azathioprine or purinethol) is added as maintenance treatment. In a subset of patients, treatment with biologicals is required. Investigations of dysbiosis of the gut microbiota in patients with IBD may guide the development of new therapeutic strategies. IBD is characterized by a disturbed gut microbiota. Importantly, fecal microbiota transplantation (FMT) is able to induce remission in a small subset of patients with active ulcerative colitis (1-4). Interestingly, certain donors may be more effective, and patients with a response after FMT showed a change of their mlcrobiota profile towards that of their donor, pointing to the potential benefit of careful donor selection (1). So far, FM7 was been studied as induction therapy in patients with active inflammation without pre-treatment with antiinflammatory medication. The active inflammation may in part explain the side effects of FMT described ín IBO patients, such as fever, increased CRP and bacteraemia. Furthermore, the active inflammation may negatively influence engraftment of donor microbiota, which could possibly explain the limited efficacy of FMT in IBD patients. Our hypothesis is that the efficacy of FMT in patients with active ulcerative colitis can be increased by: 1. Pre treatment with budesonide (sortiment, which is a standard treatment approach in patients with activity of ulceratnre colitis) to enhance engraftment of donor microbiota in the recipient 2. Rational donor selection increases the effectiveness of FMT in patients with FMT

Our hypothesis is that the efficacy of FMT in patients with active UC can be increased by: 1. Pretreatment with budesonide in patients with active UC, which may reduce inflammation prior to infusion of the donor feces solution. This reduced inflammation may enable more effective engraftment of donor microbiota in the recipient, thereby increasing the efficacy of FMT. Treatment with cortiment is a standard treatment approach in patients with active ulcerative colitis. This study compares two different approaches in timing of FMT: (1) after initiation of anti-inflammatory therapy with budesonide or (2) without/before initiation of anti-inflammatory therapy with budesonide. 2. Rational donor selection. This might increase the power of FMT by preferentially transferring beneficial microbiota.

Baseline: randomization, starting with the pre-treatment (placebo vs. Budesonide), first visit at the outpatient clinic Week 3: FMT 1 Week 4: FMT 2 Week 5: FMT 3 Week 6: FMT 4 Week 7: collecting samples Week 8: collecting samples Week 10 (4 weeks after the last FMT): follow-up visit at the outpatient clinic Week 14 (8 weeks after the last FMT): follow-up visit at the outpatient clinic Week 15: Sigmoidoscopy

Patients with active ulcerative colitis (n=24) will be randomized to a 3 weeks course of budesonide 9 mg once a day or placebo, followed by 4 infusions of a donor feces solution produced by the NDFB. The first FMT will be scheduled immediately after cessation of budesonide or placebo (t=3 weeks) and is delivered by a nasoduodenal tube. Three subsequent FMTs are scheduled weekly. Each individual patient receives donor feces infusion of one donor. Patients are treated with bowel lavage one day prior to the first FMT. Bowel lavage is not given prior to the 2nd, 3rd and 4th FMT Sigmoidoscopy will be performed 8 weeks after the 4th FMT, or earlier in case of clinical suspicion of persistent or recurrent activity.